Polymers of fluorinated monomers and hydrocarbon monomers

ABSTRACT

It is provided a polymer blend that contains a polymer formed of fluorinated monomers and hydrocarbon monomers and another biocompatible polymer.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional application of U.S. application Ser. No.11/021,775, filed on Dec. 22, 2004, now U.S. Pat. No. 7,604,818, theteaching of which is incorporated herein it its entirety by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a polymeric material useful forcoating an implantable device, such as a stent.

2. Description of the Background

Although stents work well mechanically, the chronic issues of restenosisand, to a lesser extent, stent thrombosis remain. Pharmacologicaltherapy in the form of a drug-delivery stent appears a feasible means totackle these biologically derived issues. Polymeric coatings placed ontothe stent serve to act both as the drug reservoir, and to control therelease of the drug. One of the commercially available polymer coatedproducts is a stent manufactured by Boston Scientific. For example, U.S.Pat. Nos. 5,869,127; 6,099,563; 6,179,817; and 6,197,051, assigned toBoston Scientific Corporation, describe various compositions for coatingmedical devices. These compositions provide to stents described thereinan enhanced biocompatibility and may optionally include a bioactiveagent. U.S. Pat. No. 6,231,590 to Scimed Life Systems, Inc., describes acoating composition, which includes a bioactive agent, a collagenousmaterial, or a collagenous coating optionally containing or coated withother bioactive agents.

The nature of the coating polymers plays an important role in definingthe surface properties of a coating. For example, a very low T_(g),amorphous coating material induces unacceptable rheological behaviorupon mechanical perturbation such as crimping, balloon expansion, etc.On the other hand, a high T_(g), or highly crystalline coating materialintroduces brittle fracture in the high strain areas of the stentpattern. Furthermore, a very low T_(g), amorphous coating material canhave a high drug permeability leading to an unacceptably high drugrelease rate. While a high T_(g), or highly crystalline coating materialcan have a very low polymer permeability, which lead to an unacceptablylow drug release rate. These are general principles which must also becombined with the properties of the drug such as the drug solubility inthe polymer and in the tissue.

Some of the currently used polymeric materials have some undesirableproperties such as lack of sufficient elongation to use on a stent orlow permeability to drugs. One such polymer is poly(vinylidene fluoride)(PVDF). Therefore, there is a need for new polymeric materials suitablefor use as coating materials on implantable devices.

The present invention addresses such problems by providing a polymericmaterial for coating implantable devices.

SUMMARY OF THE INVENTION

Provided herein is a polymer containing fluorinated monomers andhydrocarbon monomers useful for coating an implantable device such as astent. The fluorinated monomers can provide mechanical strength for thepolymer. The hydrocarbon monomers described herein impart flexibility tothe polymer.

In one embodiment, the polymer can be a random or block polymer having ageneral formula as shown below (Formula I):

where m and n can be positive integers ranging from 1 to 100,000.

The fluoro monomers are generally fluorinated alkylene monomers and canbe unsubstituted or substituted fluorinated ethylene. In one embodiment,the fluoro monomer is a substituted fluorinated ethylene bearing asubstituent (R) such as —CF₂—CRF—, —CHF—CRF—, —CH₂—CRF—, —CF₂—CRH—, and—CFH—CRH—. R can be hydrogen, Cl, Br, I, methyl, ethyl, n-propyl,isopropyl, short chain alkyl groups, phenyl, substituted phenyl, cyclicalkyl, heterocyclic, heteroaryl, fluorinated short chain alkyl groups,fluorinated phenyl, fluorinated cyclic alkyl, fluorinated heterocyclic,or combinations thereof. Some exemplary fluorinated alkylene monomersinclude tetrafluoroethylene, trifluoroethylene, vinylidene fluoride,chlorotrifluoroethylene, pentafluoropropene, hexafluoropropene, vinylfluoride, and —CHF—CHF—.

The hydrocarbon monomers can be any hydrocarbon vinyl monomers orsubstituted hydrocarbon vinyl monomers capable of forming biocompatiblepolymers. The hydrocarbon vinyl monomers generally have the formulaeCHR═CH₂ or CR₂═CH₂ in which R can be hydrogen, methyl, ethyl, n-propyl,isopropyl, short chain alkyl groups, phenyl, substituted phenyl, cyclicalkyl, heterocyclic, heteroaryl, or combinations thereof. Representativehydrocarbon vinyl monomers include isobutylene, styrene, methyl styrene,and alkyl substituted styrene. Other hydrocarbon monomers that willyield biocompatible polymers include, but are not limited to, ethylene,propylene, and butylene.

In another embodiment, the hydrocarbon monomer can be a non vinylmonomer. Useful non vinyl monomers include CHR═CHR or CR₂═CHR in which Rcan be methyl, ethyl, n-propyl, isopropyl, short chain alkyl groups,phenyl, substituted phenyl, cyclic alkyl, heterocyclic, heteroaryl, orcombinations thereof. Representative non vinyl monomers include, but arenot limited to, 2-butylene, 2-pentene, 2-hexene, and 3-hexene.

In the polymer of Formula I, the fluoro monomers generally account forabout 25.01 mole % to about 99.99 mole %, or more narrowly, 50.01 mole %to about 94.99% of the total monomers forming the polymer, and thehydrocarbon monomers generally account for about 0.01 mole % to about74.99 mole % mole %, or more narrowly 5.01 mole % to about 49.99 mole %of the total monomers forming the polymer. By varying the molepercentages of the two components of the polymer, one can fine-tunephysical properties of the polymer. The polymer described herein can bea random or block copolymer.

In another embodiment, it is provided a polymer blend that includes apolymer that has fluorinated monomers and at least one otherbiocompatible polymer. In one embodiment, the polymer that hasfluorinated monomers has a structure of Formula I as defined above.

The polymer or polymer blends described herein, optionally with abioactive agent, can be used to form an implantable device such as astent or coating(s) on an implantable device such as a stent. Someexemplary bioactive agents are paclitaxel, docetaxel, estradiol, nitricoxide donors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, andcombinations thereof. The implantable device can be implanted in apatient to treat, prevent or ameliorate a disorder such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

DETAILED DESCRIPTION

Provided herein is a polymer containing fluorinated monomers andhydrocarbon monomers. The fluorinated monomers can provide mechanicalstrength for the polymer. The hydrocarbon monomers impart flexibility tothe polymer. The polymer or polymer blends described herein, optionallywith a bioactive agent, can be used to form an implantable device suchas a stent or coating(s) on an implantable device such as a stent. Someexemplary bioactive agents are paclitaxel, docetaxel, estradiol, nitricoxide donors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, andcombinations thereof. The implantable device can be implanted in apatient to treat, prevent or ameliorate a disorder such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

Polymers of Fluorinated Monomers and Hydrophilic Monomers

In one embodiment, the polymer can be a random or block polymer having ageneral formula as shown below (Formula I):

where m and n can be positive integers ranging from, e.g., 1 to 100,000.

The fluoro monomers are generally fluorinated alkylene monomers and canbe unsubstituted or substituted fluorinated ethylene. In one embodiment,the fluoro monomer is a substituted fluorinated ethylene bearing asubstituent (R) such as —CF₂—CRF—, —CHF—CRF—, —CH₂—CRF—, —CF₂—CRH—, and—CFH—CRH—. R can be hydrogen, Cl, Br, I, methyl, ethyl, n-propyl,isopropyl, short chain alkyl groups, phenyl, substituted phenyl, cyclicalkyl, heterocyclic, heteroaryl, fluorinated short chain alkyl groups,fluorinated phenyl, fluorinated cyclic alkyl, fluorinated heterocyclic,or combinations thereof. Some exemplary fluorinated alkylene monomersinclude tetrafluoroethylene, trifluoroethylene, vinylidene fluoride,chlorotrifluoroethylene, pentafluoropropene, hexafluoropropene, vinylfluoride, and —CHF—CHF—.

The hydrocarbon monomers can be any hydrocarbon vinyl monomers orsubstituted hydrocarbon vinyl monomers capable of forming biocompatiblepolymers. The hydrocarbon vinyl monomers generally have the formulasCHR═CH₂ or CR₂═CH₂ in which R can be hydrogen, methyl, ethyl, n-propyl,isopropyl, short chain alkyl groups, phenyl, substituted phenyl, cyclicalkyl, heterocyclic, heteroaryl, or combinations thereof. Representativehydrocarbon vinyl monomers include isobutylene, styrene, methyl styrene,and alkyl substituted styrene. Other hydrocarbon monomers that willyield biocompatible polymers include, but are not limited to, ethylene,propylene, butylene.

In the polymer of Formula I, the fluoro monomers generally account forabout 25.01 mole % to about 99.99 mole %, or more narrowly, 50.01 mole %to about 94.99% of the total repeating units forming the polymer, andthe hydrocarbon monomers generally account for about 0.01 mole % toabout 74.99 mole % mole %, or more narrowly 5.01 mole % to about 49.99mole % of the total repeating units forming the polymer. By varying themole percentages of the two components of the polymer, one can fine-tunephysical properties of the polymer. The polymer described herein can bea random or block copolymer.

In one embodiment, the polymer of formula I has a structure of formulaII or formula III:

The polymer described herein can be synthesized by methods known in theart (see, for example, D. Braun, et al., Polymer Synthesis: Theory andPractice. Fundamentals, Methods, Experiments. 3^(rd) Ed., Springer,2001; Hans R. Kricheldorf, Handbook of Polymer Synthesis, Marcel DekkerInc., 1992). For example, one method that can be used to make thepolymer can be free radical methods (see, for example, D. Braun, et al.,Polymer Synthesis: Theory and Practice. Fundamentals, Methods,Experiments. 3^(rd) Ed., Springer, 2001; Hans R. Kricheldorf, Handbookof Polymer Synthesis, Marcel Dekker Inc., 1992). Polymerization insolvent can also be used to synthesize the polymer described herein.

Copolymerization prevents phase separation on a large scale. For systemswhere the reactivity ratios greatly differ, a random polymerization willresult in more and more of a block structure. Otherwise, polymerizationsthat proceed step-wise via the formation of prepolymers may be used toachieve block structures (See, for example, J. Kopecek, et al., Prog.Polym. Sci, 9:34 (1983)).

Polymer Blends

In another embodiment, the polymer of formulae I-III can be blended withanother biocompatible polymer to form a coating material for animplantable device. The biocompatible polymer can be biodegradable ornondegradable. Representative examples of these biocompatible polymersinclude, but are not limited to, poly(ester amide), polyesters,polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalknaotes) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyurethanes, polyphosphazenes,silicones, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, poly(methylmethacrylate), poly(ethyl methacrylate),poly(isopropyl methacrylate), poly(n-propyl methacrylate), poly(n-butylmethacrylate), methacrylic polymers and copolymers, acrylic polymers andcopolymers, vinyl halide polymers and copolymers, such as polyvinylchloride, poly(vinylidene fluoride), poly(vinylidenefluoride-co-hexafluoropropylene), polyvinyl ethers such as polyvinylmethyl ether, polyvinylidene halides such as polyvinylidene chloride,polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such aspolystyrene, polyvinyl esters such as polyvinyl acetate, copolymers ofvinyl monomers with each other and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 andpolycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, poly(glyceryl sebacate), poly(propylenefumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters), e.g., copoly(ethylene oxide-co-lactic acid)(PEO/PLA), polyalkylene oxides such as poly(ethylene oxide) andpoly(propylene oxide), polyalkylene oxalates, phosphoryl choline,choline, poly(aspirin), polymers and co-polymers of hydroxyl bearingmonomers such as hydroxyethyl methacrylate (HEMA), hydroxypropylmethacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA),PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) andn-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such asmethacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, collagen, dextran, dextrin, fragments and derivativesof hyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, and combinations thereof. In some embodiments, thepolymer can exclude any one of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide) (PDLL), poly(L-lactide)(PLL), poly(D,L-lactide-co-glycolide) (PDLLG), andpoly(L-lactide-co-glycolide) (PLLG) are used interchangeably with theterms poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA),poly(D,L-lactic acid-co-glycolic acid) (PDLLAGA), and poly(L-lacticacid-co-glycolic acid) (PLLAGA), respectively.

Bioactive Agents

In accordance with a further embodiment of the invention, the polymer orpolymer blend described herein can form a coating that may optionallyinclude one or more active agents. The bioactive agent can be any agentthat is biologically active, for example, a therapeutic, prophylactic,or diagnostic agent.

Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules which bind tocomplementary DNA to inhibit transcription, and ribozymes. Compoundswith a wide range of molecular weight can be encapsulated, for example,between 100 and 500,000 grams or more per mole. Examples of suitablematerials include proteins such as antibodies, receptor ligands, andenzymes, peptides such as adhesion peptides, saccharides andpolysaccharides, synthetic organic or inorganic drugs, and nucleicacids. Examples of materials which can be encapsulated include enzymes,blood clotting factors, inhibitors or clot dissolving agents such asstreptokinase and tissue plasminogen activator, antigens forimmunization, hormones and growth factors, polysaccharides such asheparin, oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. The polymercan also be used to encapsulate cells and tissues. Representativediagnostic agents are agents detectable by x-ray, fluorescence, magneticresonance imaging, radioactivity, ultrasound, computer tomagraphy (CT)and positron emission tomagraphy (PET). Ultrasound diagnostic agents aretypically a gas such as air, oxygen or perfluorocarbons.

In the case of controlled release, a wide range of different bioactiveagents can be incorporated into a controlled release device. Theseinclude hydrophobic, hydrophilic, and high molecular weightmacromolecules such as proteins. The bioactive compound can beincorporated into polymeric coating in a percent loading of between0.01% and 70% by weight, more preferably between 5% and 50% by weight.

In one embodiment, the bioactive agent can be for inhibiting theactivity of vascular smooth muscle cells. More specifically, thebioactive agent can be aimed at inhibiting abnormal or inappropriatemigration and/or proliferation of smooth muscle cells for the inhibitionof restenosis. The bioactive agent can also include any substancecapable of exerting a therapeutic or prophylactic effect in the practiceof the present invention. For example, the bioactive agent can be forenhancing wound healing in a vascular site or improving the structuraland elastic properties of the vascular site. Examples of active agentsinclude antiproliferative substances such as actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233, or COSMEGEN available fromMerck). Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The bioactive agentcan also fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel, (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, proteins, peptides, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents includealpha-interferon, genetically engineered epithelial cells,anti-inflammatory agents, steroidal anti-inflammatory agents,non-steroidal anti-inflammatory agents, antivirals, anticancer drugs,anticoagulant agents, free radical scavengers, estradiol, antibiotics,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, cytostatic agents, prodrugs thereof, co-drugsthereof, or a combination thereof.

The foregoing substances are listed by way of example and are not meantto be limiting. Other active agents which are currently available orthat may be developed in the future are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent required to inhibit the desired cellular activityof the vascular region can depend upon factors such as the particularcircumstances of the patient; the nature of the trauma; the nature ofthe therapy desired; the time over which the ingredient administeredresides at the vascular site; and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, closure devices for patent foramen ovale,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads(e.g., FINELINE and ENDOTAK, available from Guidant Corporation, SantaClara, Calif.). The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108,cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromStandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will retain on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate, and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, atherosclerosis, thrombosis, and restenosis. Stentsmay be placed in a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, carotid, andcoronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter, whichallows a stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously, orby surgery, into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth prophetic examples. All parameters and data are notto be construed to unduly limit the scope of the embodiments of theinvention.

Example 1 Synthesis of poly(block-vinylidenefluoride-co-block-isobutylene)

Fluoropolymers are typically synthesized by free radical polymerization,using suspension or emulsion techniques, while polyisobutylene istypically produced via cationic polymerization methods (see G. Odian,Principles of Polymerization, 3^(rd) Ed., John Wiley & Sons, NY, 1991).However, fluoropolymers can also be synthesized by atom transfer radicalpolymerization (ATRP) using iodine or bromine functional initiators.These polymerizations result in PVDF with terminal iodine or brominegroups. These endgroups can then be used directly, or functionalized, toserve as carbocationic initiators for isobutylene. A block co-polymercan be made by first synthesizing a bromo-terminated poly(vinylidenefluoride) via ATRP techniques (see Z. Zhang, et al. “Synthesis offluorine-containing block copolymers via ATRP 1. Synthesis andcharacterization of PSt-PVDF-PSt triblock copolymers”, Polymer (40)(1999) 1341-1345). The resulting bromo-terminated PVDF can then be usedas an initiator in a cationic polymerization catalyzed by a lewis acidsuch as titanium tetrachloride, titanium tetrabromide, or aluminumtrichloride (see J. P. Kennedy, et al. “Design Polymers by carbocationicMacromolecular Engineering”, Hanser, N.Y., Munich, 1992). A usefulweight ratio of vinylidene fluoride to isobutylene is 75/25.

Example 2 Synthesis of poly(vinylidene fluoride-co-styrene)

Both monomers are amenable to free radical polymerization. Thispolymerization can be via suspension or emulsion polymerizationtechniques. Useful initiators are peroxides, organic soluble peroxides,persulfate compounds, and azo compounds. Redox systems such as compoundscontaining ferrous, sulfite, or bisulfite ions can be used to producedesirable initiation rates at low temperatures. One useful route issuspension polymerization in an autoclave. A vinylidene fluoride/styrenecopolymer dispersion can be prepared having a composition of 90%vinylidene fluoride and 10% styrene by weight. To a 10 gallonglass-lined autoclave is added 5 gallons of deionized water, and chargedwith 2.2 kg of vinylidene fluoride (VDF) and 0.24 kg of styrene. Aftersparging with nitrogen to remove all oxygen, and with rapid stirring, asolution of 20 gm of a 70% solution of tertiary butyl hydroperoxide(TBHP) that is diluted to 100 ml with deionized water is added. Next, asolution of 15 gm of sodium metabisulfite (MBS), and 2.2 gm of ferroussulfate heptahydrate, dissolved in 100 ml of deionized water is added.The autoclave is maintained at 15-20° C. After addition if the initialcatalysts, 300 ml of perfluorinated ammonium octoanate catalyst (20%active solids) is charged into the autoclave. The polymerization iscontinued by slow addition of two separate solutions consisting of 100gm of TBHP diluted to 700 ml with deionized water and 80 gm of MBSdiluted to 750 ml with deionized water. These initiators are added at arate of 1.8 ml/min. After consumption if the initial charge of VDF andstyrene, 18 kg of VDF and 2 kg of styrene are added over a period of 5hours. The autoclave is vented, yielding a polymer dispersion in waterwhich is isolated by sieving and rinsed.

Example 3 Coating a Stent with the Composition of Example 2

A composition can be prepared by mixing the following components:

(a) about 2.0% (w/w) of poly(butyl methacrylate) (PBMA), and

(b) the balance a 50/50 (w/w) blend of acetone and cyclohexanone. Thecomposition can be applied onto the surface of bare 12 mm small VISION™stent (Guidant Corp.). The coating can be sprayed and dried to form aprimer layer. A spray coater can be used having a 0.014 round nozzlemaintained at ambient temperature with a feed pressure 2.5 psi (0.17atm) and an atomization pressure of about 15 psi (1.02 atm). About 20 μgof the coating can be applied at per one spray pass. About 80 μg of wetcoating can be applied, and the stent can be dried for about 10 secondsin a flowing air stream at about 50° C. between the spray passes. Thestents can be baked at about 80° C. for about one hour, yielding a drugreservoir layer composed of approximately 60 μg of PBMA.

A second composition can be prepared by mixing the following components:

(a) about 2.0% (w/w) of the polymer of example 2;

(b) about 1.0% (w/w) of everolimus,

(c) the balance a 50/50 (w/w) blend of acetone and dimethylformamide.

The second composition can be applied onto the dried primer layer toform a drug reservoir layer using the same spraying technique andequipment used for applying the reservoir. About 200 μg of wet coatingcan be applied followed by drying and baking at about 50° C. for about 2hours, yielding a dry drug reservoir layer having solids content ofabout 180 μg and containing about 60 μg of everolimus.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A polymer blend comprising a random biocompatiblepolymer and at least one other biocompatible polymer, wherein the randombiocompatible polymer comprises fluorinated monomers and hydrocarbonmonomers, wherein the hydrocarbon monomers are CHR═CH₂ in which R isselected from the group consisting of phenyl, substituted phenyl, cyclicalkyl, heterocyclic alkyl, and heteroaryl, or CR′₂═CH₂ in which R′ isselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, short chain alkyl groups, phenyl, substituted phenyl, cyclicalkyl, heterocyclic alkyl, and heteroaryl, wherein the fluorinatedmonomers are selected from the group consisting of —CF₂—CF₂—, —CH₂—CF₂—,—CH₂—CHF—, —CHF—CHF—, —CClF—CF₂—, —CF₂—C(CF₃)F—, —CHF—C(CF₃)F—,—CF₂—C(CF₃)H—, —CF₂—CR″F—, —CHF—CR″F—, —CF₂—CR″H—, —CH₂—CR″F— and—CFH—CR″H—, where R″ is independently selected from the group consistingof hydrogen, Cl, Br, I, methyl, ethyl, n-propyl, iosopropyl, short chainalkyl groups, phenyl, substituted phenyl, cyclic alkyl, heterocyclic,heteroaryl, fluorinated short chain alkyl groups, fluorinated phenyl,fluorinated cyclic alkyl, fluorinated heterocyclic, and combinationsthereof, wherein the fluorinated monomers form about 25.01 mole % toabout 99.99 mole % repeating units of the polymer, and wherein thehydrocarbon monomers form about 74.99 mole % to about 0.01 mole %repeating units of the polymer.
 2. The polymer blend of claim 1, whereinthe fluorinated monomers form about 50.01 mole % to about 94.99 mole %units of the polymer, and wherein the hydrocarbon monomers form about49.99 mole % to about 5.01 mole % repeating units of the polymer.
 3. Thepolymer blend of claim 1, wherein the other biocompatible polymer isselected from the group consisting of poly(ester amide), polyesters,polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates),poly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate),poly(4-hydroxyalknaotes), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) copolymers including3-hydroxyalkanoate, 4-hydroxyalkanoate monomers described herein orblends thereof, poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),polycaprolactone, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,polyphosphazenes, silicones, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, methacrylic polymers and copolymers,acrylic polymers and copolymers, poly(methylmethacrylate), poly(ethylmethacrylate), poly(isopropyl methacrylate), poly(n-propylmethacrylate), poly(n-butyl methacrylate), vinyl halide polymers andcopolymers polyvinyl chloride, polyvinyl ethers, polyvinyl methyl ether,polyvinylidene halides, polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics, polystyrene, polyvinyl esters,polyvinyl acetate, copolymers of vinyl monomers, ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers, polyamides, Nylon 66 andpolycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, poly(glyceryl sebacate), poly(propylenefumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers, poly(ethylene glycol) (PEG),copoly(ether esters), copoly(ethylene oxide-co-lactic acid) (PEO/PLA),polyalkylene oxides, poly(ethylene oxide), poly(propylene oxide),polyalkylene oxalates, phosphoryl choline, choline, poly(aspirin),polymers and co-polymers of hydroxyl bearing monomers, polymers andcopolymers of hydroxyethyl methacrylate (HEMA), polymers and copolymersof hydroxypropyl methacrylate (HPMA), polymers and copolymers ofhydroxypropylmethacrylamide, polymers and copolymers of PEG acrylate(PEGA), polymers and copolymers of PEG methacrylate, polymers andcopolymers of 2-methacryloyloxyethylphosphorylcholine (MPC), polymersand copolymers of n-vinyl pyrrolidone (VP), polymers and copolymers ofcarboxylic acid bearing monomers, polymers and copolymers of methacrylicacid (MA), polymers and copolymers of acrylic acid (AA), polymers andcopolymers of alkoxymethacrylate, polymers and copolymers ofalkoxyacrylate, polymers and copolymers of 3-trimethylsilylpropylmethacrylate (TMSPMA), poly(styrene-isoprene-styrene)-PEG (SIS-PEG),polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG),PLA-PEG, poly(methyl methacrylate)-PEG (PMMA-PEG),polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene fluoride)-PEG(PVDF-PEG), PLURONIC™ surfactants (polypropylene oxide-co-polyethyleneglycol), poly(tetramethylene glycol), hydroxy functional poly(vinylpyrrolidone), biomolecules, collagen, chitosan, alginate, fibrin,fibrinogen, cellulose, starch, collagen, dextran, dextrin, fragments andderivatives of hyaluronic acid, heparin, fragments and derivatives ofheparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide,elastin, chitosan, alginate, and combinations thereof.
 4. The polymerblend of claim 1, wherein the hydrocarbon monomer is selected from thegroup consisting of one or more isobutylene, styrene, methyl styrene,and alkyl substituted styrene.
 5. The polymer blend of claim 1, whereinthe random biocompatible polymer has a structure of any of formulaeII-III:

wherein m and n are positive integers ranging from 1 to 100,000.